Review
Feature Review
The histone shuffle: histone chaperones in an energetic dance

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Our genetic information is tightly packaged into a rather ingenious nucleoprotein complex called chromatin in a manner that enables it to be rapidly accessed during genomic processes. Formation of the nucleosome, which is the fundamental unit of chromatin, occurs via a stepwise process that is reversed to enable the disassembly of nucleosomes. Histone chaperone proteins have prominent roles in facilitating these processes as well as in replacing old histones with new canonical histones or histone variants during the process of histone exchange. Recent structural, biophysical and biochemical studies have begun to shed light on the molecular mechanisms whereby histone chaperones promote chromatin assembly, disassembly and histone exchange to facilitate DNA replication, repair and transcription.

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Histone chaperones

The nucleosome hypothesis for chromatin, proposed by Don and Ada Olins and Roger Kornberg in 1974 1, 2, was a paradigm shift for research into eukaryotic genomic processes. We now know that chromatin comprises a repeated array of nucleosome core particles of approximately 147 bp DNA wound 1.7 times around the outside of a core histone octamer which includes two molecules each of histone proteins H2A, H2B, H3 and H4 (Box 1) separated by varying lengths of linker DNA which can be associated with

The need for histone chaperones

From an energetic standpoint, arguably the largest transitions in chromatin dynamics occur during the processes of assembling and disassembling nucleosomes, and not surprisingly, the assembly and disassembly of nucleosomes occurs in a stepwise fashion. It has been generally accepted that some form(s) of the pathway illustrated in Figure 1 operates to construct nucleosomes from component histone dimer precursors (Box 1). The pathway includes the assembly of H3–H4 dimers into H3–H4 tetramers, a

Structural forms of histone chaperones

Histone chaperones are as varied as the processes they promote. Many specialized chaperones for the histones that form the nucleosome core particle (core histones) and those that interact with the nucleosome core and the linker DNA (linker histones) participate at each step in the processes of nucleosome assembly, disassembly and histone exchange during different genomic processes (Table 1) 11, 14. Additionally, specific variant histone chaperones, such as yeast Chz1 and Yaf9, recruit H2AZ,

Implications of oligomeric status of histone chaperones and the surfaces of the histones to which they bind

Several themes have emerged from detailed analyses of histone chaperones. They have different oligomeric states that correlate with their roles in different stages of nucleosome assembly. Moreover, they show a variety of multimeric interactions that involve different regions of the chaperones and different regions of the histones (Table 2). There are generally two types of histone chaperone–histone binding: simple 1:1 or 2:2 with affinity values in the range of 1–100 nM and multimeric histone

The nucleosome assembly process

Multiple steps, in parallel pathways, lead to the formation of the ultimate product of chromatin assembly – the nucleosome core particle (Figure 3). The incorporation of specific histone post-translational modifications and the hand-off or ‘shuffle’ of the histones between histone chaperones are common themes along these pathways. Histones H2A–H2B and H3–H4 are delivered via distinct pathways that usually utilize distinct histone chaperones, coming together only on the DNA.

Arguably the earliest

Disassembly of nucleosomes

Chromatin disassembly appears to be the stepwise opposite of the assembly process with one major difference [42] being that nucleosome disassembly is an intrinsically energetically unfavorable process. The requirement for ATP-dependent chromatin remodeling complexes for chromatin disassembly is understandable [42], given the need to break the histone–DNA contacts to allow removal of the histones by the histone chaperones. Although the basic steps and players are beginning to be uncovered, there

Histone chaperone-guided folding pathways

The histone hand-off during assembly must be energetically favorable. Although it is convenient to think of nucleosome assembly as a stepwise process (Figure 1), highlighting the central role that chaperones play in the pathway, the ‘nucleosome assembly funnel’ (Figure 4) provides a thermodynamic perspective to the process. In this view, which is analogous to the protein folding problem, histone chaperones perform functions similar to those of protein folding chaperones in guiding the folding

Concluding remarks

Histone chaperones are key players involved in maintaining histone stability and dynamics in the cell. Structural, biophysical and biochemical information on histone chaperones is beginning to shape a new understanding of the integrated mechanisms of action for this important family of proteins (Box 2). The varied structural motifs and oligomeric states drive electrostatic and conformation-specific interactions between histone chaperones and different faces of the histones, resulting in a

Acknowledgments

Owing to limitations on the number of references, we were unable to directly cite all of the relevant literature, and many relevant references can be found within the cited references. We are grateful to members of the Churchill and Tyler labs for their suggestions for the manuscript. We are especially grateful to Siddhartha Roy for assistance with the figures. We acknowledge support from NIH GM and NCI to J.K.T., NIH GM to M.E.A.C. and a Susan Komen Fellowship to C.D.

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